In a huge international study, an experimental drug for heart failure worked dramatically better than the current backbone of treatment, paving the way for the biggest therapeutic advance in decades.

Novartis' twice-a-day pill, still known by its code name, LCZ696, reduced deaths, hospitalizations, and disabling symptoms of heart failure. It also had fewer serious side effects than the standard therapy, a blood-pressure-lowering medication called enalapril.

"We designed this study to try to change the cornerstone of treatment - to replace enalapril," said the study's lead co-author, Milton Packer, a cardiologist and heart failure researcher at the University of Texas Southwestern Medical Center. "The results are not only compelling but exceeded our expectations."

In an editorial accompanying the study, published online Saturday in the New England Journal of Medicine, University of Pennsylvania cardiologist Mariell Jessup wrote that the novel therapy may "represent a new threshold of hope for patients with heart failure."

Heart failure, the only cardiovascular disease on the rise, affects 5 million people in the U.S. Worldwide, the economic toll is estimated at $45 billion.

A progressive disorder, it begins when heart cells are injured by a heart attack, infection, chemotherapy, or other causes. Healthy cells try to compensate by overworking and enlarging while the body retains water and increases blood pressure in a futile effort to improve blood flow.

Until the 1980s, the standard treatments - digoxin, which strengthens heart contractions, and diuretics, which increase urine output - did nothing to reduce mortality, and little to relieve the symptoms of breathlessness, fatigue, and swelling.

Then came enalapril, approved in 1985, the second in a class of drugs called ACE inhibitors. These compounds, which lower blood pressure by widening blood vessels, improved symptoms and survival. Further progress was made by combining ACE inhibitors with drugs that block adrenaline, as well as more sophisticated diuretics.

Even with all this and more - heart failure patients typically take four to eight drugs - about 50 percent died within five years.

The latest advance involves blocking an enzyme, neprilysin, that plays a key role in the complex process of blood vessel constriction, fluid retention, and heart enlargement that makes the heart gradually fail.

"This is a new pathway. That's what's really exciting," Jessup said, adding that other pharmaceutical companies were developing their own anti-neprilysin compounds.

Novartis' new drug combines its neprilysin inhibitor with valsartan, a blood-pressure-lowering drug that works somewhat differently from enalapril.

The pivotal study, begun in 2009, enrolled 8,400 patients with mild to moderately severe heart failure at more than 1,000 centers around the world, making it the largest clinical trial in heart failure ever undertaken. The patients were randomly assigned to take LCZ696 or enalapril, plus other medications that were part of their prescribed regimen.

The trial was stopped early, after following patients for a median of 27 months, because the new drug met criteria for "overwhelming benefit."

Of 4,187 patients on the new drug, 914 died from cardiovascular causes or were hospitalized for worsening heart failure - 21.8 percent of the group. That compared to 1,117 deaths and hospitalizations (26.5 percent) among 4,212 people taking enalapril.

The Novartis drug was also better tolerated. Slightly less than 11 percent quit it because of side effects such as dangerously low blood pressure or worsening kidney function, compared to about 12 percent for enalapril.

On a questionnaire, patients taking LCZ696 reported more improvement in heart failure symptoms and physical limitations than the comparison group.

Novartis will now ask the U.S. Food and Drug Administration to approve the drug based on the results.

Will it become the new linchpin of heart failure treatment?

"I think it might," said University of Pennsylvania cardiologist Lee R. Goldberg, who chairs the American College of Cardiology's heart failure group. "We'll need to see how well the drug is tolerated. But certainly this clinical trial suggests it's superior to enalapril."